The present invention relates to the preparation of indoles from the palladium catalyzed reaction of 2-halo- and 2-trifluoromethylsulfonyloxy-anilines and ketones. In one embodiment of the present invention, substituted alkyl ketones are employed. This embodiment is particularly useful in preparing 2, 3, di-substituted indole derivatives, useful in the preparation of indomethacin and certain lipoxygenase inhibitors. Thus, the process of the present invention is useful in preparing biologically active compounds.
Generally, indoles are prepared via the Fischer-indole reaction. For example, Chen et al., J. Org. Chem., 59:3738 (1994) disclose the preparation of N,N-dimethyl tryptamines from 4-substituted hydrazines and dimethylaminobutyraldehyde dimethyl acetal using 4% H.sub.2 SO.sub.4. However, the yields are often low, particularly for compounds having triazole substitution. Benzyltriazoles are unstable to the Fischer indole reaction conditions, which generally lead to polymerization of the triazole moiety, and the production of oligomers.
Chen et al., Tet. Lett. 35:6981 (1994) describe basic/neutral coupling to form indoles employing hydrazines. Hydrazines are inherently less stable than the amines (anilines) employed in the present invention.
In contrast, the present invention provides for a robust process that occurs under mild conditions.
Iida et al., J. Org. Chem. 45:2938-2942 (1980) describe intramolecular cyclization of 3-((2-bromoaryl)amino) cyclohex-2-en-1-ones with catalytic palladium in the presence of triphenyl phosphine, as well as the reaction of aryl amines with .beta.-diketones to form the corresponding secondary enaminone followed by N-ethylation to form the corresponding tertiary enaminones and subsequent intramolecular cyclization in the presence of equimolar palladium acetate.
Sakamota et al., Synthesis, p. 215-218 (1990), describe palladium-catalyzed cyclization of .beta.-(2-halophenyl)amino substituted .alpha.,.beta.-unsaturated ketones and esters to produce 2,3-disubstituted indoles. The procedure of Sakamota et al., also employs phosphine. Further, the Sakamoto method requires a 1,3-diketone. The process of the present invention employs a mono-ketone.
Indole is a common feature of a variety of natural products, many of which possess potent biological activities. Hence, indoles are attractive synthetic targets. When substituted alkyl ketones are employed in the process of the present invention, the present invention has particular application in the synthesis of 2,3-disubstituted indoles, including the precursor to indomethacin, shown below. ##STR2##
When cyclic ketones are employed in the process of the present invention, the present invention has particular application in the synthesis of tetrahydrocarbazole derivatives and homologs and analogs thereof. In particular, the precursor to the antidepressant iprindole may be made according to the process of the present invention. ##STR3##
Thus, the present invention also provides for an efficient and cost-effective synthesis of pharmaceutically active indole derivatives useful in the treatment of disease.